Dysfunctional healing CAN involve a slowing of the process, which can lead to indolent and chronic wounds. Such slowing can be due to factors such as hemorrhagic shock, infection, immune suppression, or prolonged psychological distress. Alternatively, dysfunctional healing can involve a hyperproliferative response, which can lead to, e.g., post-surgical adhesions.
Macrophages are central to the complex process of wound healing, which involves removal of dead tissue, formulation of granulation tissue, neovascularization, stimulation of locomotion and proliferation of fibroblasts and keratinocytes, and production of collagen types I and III. Photodynamic therapy can destroy large amounts of tissue with a good healing response and good cosmetic result (Koren et al, Int. J. Radiat. Oncol. Biol. Phys. 28:463-466 (1994)). Photodynamic therapy can be used either to stimulate or suppress cellular responses such as cytokine release and immune function. Whether the photodynamic therapy causes stimulation or suppresion depends on the dosage. Low dose photodynamic therapy stimulates cytokine release and immune function, while high dose photodynamic therapy suppresses those processes (Obochi et al., SPIE Proc. 2675:122-131 (1996); Yamamoto et al., Photochem. Photobiol. 60:160-164 (1994)).
Photodynamic therapy has major effects on macrophages. Low dose photodynamic therapy activates macrophages. This enhances their cytotoxicity against tumor cells (Yamamoto et al., Photobiol. B 13:295-306 (1992)). High dose photodynamic therapy leads to production of TNF alpha, and eventually, macrophage death (Evans et al., J. Natl. Cancer Inst. 82:34-39 (1990)).
Fibrosis is a response to injury in which new extracellular matrix is rapidly laid down producing dense bands of collagen that are the microscopic hallmark of scarring. The extent and duration of fibrosis often far exceeds the apparent need for wound healing, causing hypertrophic scars and contractures that limit function or distort anatomy. In the peritoneum, joints, tendon sheaths, or essentially any body space with an epithelial lining, injury and fibrosis can lead to adhesions which bind tissues together. Scars remain metabolically hyperactive long after injury, both producing and degrading extracellular matrix at a rate many times that of uninjured tissue.
The initiation and control of many concerted processes responsible for wound healing are governed by molecules which direct cell activity such as cytokines, growth factors, and adhesion molecules. In particular, the extracellular matrix growth factors TGF-.beta., platelet derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) appear to initiate and/or sustain fibrosis. Specifically TGF-.beta. appears to be the dominant cytokine governing the aggressiveness of the scarring response. TGF.beta. has been implicated in hepatic fibrosis, pulmonary fibrosis, scleroderma, and keloids. It stimulates collagen and fibronectin formation, suppresses collagenase and induces production of collagenase inhibitors. Increased TGF-.beta. levels, increasing scarring, and more rapid healing responses are associated with disorientation and thinning of type I collagen fibers with abnormal production of proteoglycans and glycosaminoglycans in wound extracellular matrix.
Photodynamic therapy has been used to treat cancer. See, e.g., Dougherty et al., In Photodynamic Therapy of Neoplastic Disease, (Kessel, ed.), CRC Press, Boca Raton, Fla. (1989). Photodynamic therapy has also been used for destruction of the synovium in the treatment of rheumatoid arthritis (U.S. Pat. No. 5,368,841).